Reactivity of Stabilized Vinyldiazo Compounds toward Alkenyl- and Alkynylsilanes under Gold Catalysis: Regio- and Stereoselective Synthesis of Skipped Dienes and Enynes

We report the gold-catalyzed reaction of vinyldiazo compounds and alkenylsilanes to produce skipped dienes, which are common structural motifs in an array of bioactive compounds. This carbon–carbon bond-forming transformation proceeds with complete regio- and stereoselectivity with the silyl group serving as a regio- and stereocontrolling element. Likewise, the use of alkynylsilanes as reaction partners yielded skipped enynes resulting from a C(sp)–C(sp3) coupling. Mechanistic experiments and DFT studies have provided support for a stepwise mechanism.

S ince the seminal work by Nolan, Díaz-Requejo, Peŕez and co-workers in 2005, 1 the marriage of diazo reagents with gold catalysts has proven to be an extremely fertile field of research leading to reactivity modes previously unattainable by using more traditional catalysts. 2 In this realm, initial developments focused on the use of ethyl diazoacetate and aryl substituted derivatives thereof. 3 The implementation of these gold-based methodologies to vinyldiazo compounds is more recent. Liu and co-workers in 2011 reported the synthesis of quinoline oxide derivatives through a goldcatalyzed formal [3 + 3] cycloaddition of vinyldiazo compounds with nitroso derivatives. 4 Since this pioneering study, the use of gold catalysts in transformations of vinyldiazo compounds has gained increasing interest. 5 In this regard, in the past decade, our group and others have explored the reactivity of a number of unsaturated substrates toward vinyldiazo compounds under gold catalysis (Scheme 1a). In 2013, we reported the gold-catalyzed reaction of stabilized vinyldiazo compounds and unbiased alkenes to yield 2,6-diene derivatives. 6 Despite a broad scope of alkenes, this methodology generally yields an inseparable mixture of positional isomers and E and Z stereoisomers. Concurrently, Davies and co-workers reported the highly enantioselective Au(I)catalyzed [3 + 2] cycloaddition between vinyldiazoacetates and enol ethers. 7,8 Our group also reported the regioselective synthesis of functionalized cyclopentene derivatives through the gold-catalyzed [3 + 2] cycloaddition of vinyldiazo compounds and styrenes. 9 Although a detailed mechanistic study of these transformations has not yet been undertaken, most of them have been rationalized on the basis of the initial generation of a highly electrophilic gold carbene complex, which can undergo attack of the unsaturated reagent to the vinylogous position. This vinylogous reactivity of vinyldiazo compounds had been much less common than that involving the carbenic position (Scheme 1b). 10 On the other hand, owing to their availability, nontoxic nature, and right balance between reactivity and stability, organosilicon compounds have reached an indisputable position as valuable reagents in organic synthesis. 11 In particular, vinylsilanes undergo a facile electrophilic substitution as a result of the ability of the carbon−silicon σ bond to stabilize an adjacent carbocation (the so-called β-silicon effect) (Scheme 1c). 12 We surmised that merging the electrophilic character of the postulated gold carbene intermediate generated from vinyldiazo compounds with the innate ability of vinylsilanes to undergo electrophilic-induced desilylation could enable new synthetic opportunities. Herein, we report the gold-catalyzed reaction of vinyldiazo reagents with vinylsilanes leading to functionalized skipped dienes, structural motifs found in numerous natural products and bioactive compounds. 13,14 Extension of this carbon−carbon bond formation to alkynylsilanes was also accomplished providing skipped enynes.
We began our investigation by studying the gold-catalyzed reaction of ethyl 2-diazobut-3-enoate (1a) and (E)-trimethyl-(styryl)silane (2a). Initial experiments were conducted in dichloromethane as the solvent at room temperature in the presence of 5 mol % of the corresponding gold complex. In order to overcome potential competitive side reactions, 15 slow addition of a solution of vinyldiazo reagent 1a to a solution of vinylsilane 2a (2 equiv) and the catalytic system was performed. Under these controlled addition conditions, a catalytic system composed of JohnPhosAuCl (5 mol %) and NaBAr F 4 (5 mol %, BAr 4 F− = 3,5-bis(trifluoromethyl)phenylborate) as a halide scavenger outperformed other gold(I) catalysts tested delivering (2E,5E)-6-phenylhexa-2,5dienoate (3aa) in 85% yield after chromatographic purification (eq 1; see the Supporting Information for details on the screening study). Under these conditions, the reaction could be scaled up to 1 mmol with minimal erosion of yield (75% yield, 162.2 mg).
Next, we briefly investigated the reactivity of silyl group protected enoldiazoacetates. 18 Gratifyingly, reaction of TMSprotected enoldiazoacetate 1g with silanes 2a (Ar = Ph) and 2d (Ar = p-F−C 6 H 4 ) resulted in the formation of a reaction mixture from which compounds 4ga and 4gd were obtained in 55% and 44% yield, after column chromatography (eq 2). It should be mentioned here that, along with compounds 4, diethyl 2-diazo-3,6-dioxooctanedioate (5) was also produced as a minor byproduct (8−10%). 19 Several control experiments were performed to gain insight into this coupling reaction between vinyldiazo compounds and alkenylsilanes. First, we found that conducting the model reaction in deuterated dichloromethane gave the skipped diene 3aa without incorporation of deuterium in its structure (eq 3), thus demonstrating that the extra hydrogen incorporated in the final product does not come from the solvent. Next, we conducted the model reaction in CH 2 Cl 2 as solvent in the presence of D 2 O (2 equiv). Following conventional workup, diene 3aa-D with the deuterium label incorporated exclusively in the 2-position was isolated (eq 4). Although compound 3aa-D was isolated in low yield (20%) because of partial decomposition of the starting diazo compound, this result would confirm that external water participates in the present transformation. Finally, reaction of deuterated vinyldiazo compound 1c-D with (E)-trimethyl(styryl)silane (2a) led to skipped diene 3ca-D without positional scrambling of the deuterium label (eq 5).
Based on these control experiments and previous goldcatalyzed transformations of vinyldiazo compounds, a likely mechanism is proposed in Scheme 3. The process is suggested to begin with the decomposition of the diazo derivative 1 leading to the corresponding gold carbene intermediate I, which would undergo attack of the vinylsilane 2 to the vinylogous position with generation of a carbocationic species II, stabilized by π-conjugation from the adjacent phenyl group and additionally by hyperconjugation from the TMS group placed in the β-position. Intermediate II would evolve through an intramolecular 1,4-migration of the TMS group delivering diene III, 20 which in the presence of trace amounts of water present in the reaction medium would lead to the final diene 3.
Density Functional Theory (DFT) calculations provided further support for the proposed mechanism (see the Supporting Information for details). In particular, our calculations suggest that (a) the generation of the carbene intermediate I occurs stepwise involving the migration of the transition metal fragment from the initially formed gold(I)alkene complex followed by N 2 release; (b) the formation of intermediate II can be considered as a barrierless reaction; (c) the intramolecular 1,4-migration of the TMS group is a highly exergonic concerted process which occurs with a rather low barrier of 10.3 kcal/mol; and (d) the desilylation of intermediate III to provide the final product 3 is promoted by the gold catalyst in the presence of a water molecule. According to our calculations, the high exergonicity of the process (ΔG = −27.5 kcal/mol) would be the driving force for the key intramolecular 1,4-migration of the TMS group (transformation of intermediate II into III).
The proposed mechanism would account well for the observed stereochemical outcome. Thus, the E-configuration of the fragment arising from the vinyldiazo compound would be ascribed to the preferred conformation of the carbene Organic Letters pubs.acs.org/OrgLett Letter intermediate. 21 On the other hand, the retention in the configuration of the carbon−carbon double bond of the vinylsilane is well-established and has been interpreted as a consequence of the β-silicon effect. 22 Encouraged by the results obtained with vinylsilanes, we next wondered whether alkynylsilanes could serve as suitable coupling partners, thus providing a convenient access to skipped enynes. These motifs are highly attractive because they are valuable building blocks and also structural motifs in natural products and biologically active compounds and new synthetic procedures for their synthesis would be highly desirable. 23 We first studied the reaction of ethyl 2-diazo-3-butenoate (1a) with 1-phenyl-2-trimethylsilylacetylene (6a). Gratifyingly, after a slight reoptimization of the reaction conditions, we found that using [JohnPhosAu(MeCN)][SbF 6 ] (5 mol %) as the catalyst provided ethyl (E)-6-phenylhex-2-en-5-ynoate (7aa) in 52% yield (Scheme 4).
Concerning the reaction scope of this C(sp)−C(sp 3 ) coupling, a variety of aryl-substituted trimethylsilylacetylenes 6 were subjected to the previously developed reaction conditions providing the corresponding skipped enynes 7 in moderate yields and complete regio-and stereoselectivity. As seen in Scheme 4, both alkyl groups and halogens could be accommodated in the aryl moiety. In line with the results displayed by vinylsilanes, substrates bearing strong electronwithdrawing groups performed poorly. In fact, the use of a ptrifluoromethylphenyl substituted alkynylsilane led to the corresponding skipped enyne 7af with a low yield (38%), while only traces of product 7ag were observed in the reaction of 1a with a substrate featuring a p-nitrophenyl group. In contrast, a substrate having a 3-methylphenyl group was suitable for the current reaction as illustrated by the formation of the corresponding product 7ah in moderate yield. On the other hand, a 1-naphthyl-substituted alkynylsilane could also provide the desired skipped enyne 7bi in 20% yield. Notably, alkyl-substituted alkynylsilanes also engaged in this transformation providing the corresponding skipped enynes 7aj, 7ak, and 7al in moderate yields.
According to DFT calculations, this C(sp)−C(sp 3 ) bondforming transformation is suggested to occur through the generation of a vinylic carbocation followed by a concerted intramolecular 1,4-silyl migration similar to that commented above (see Supporting Information).
In conclusion, we have devised a simple and efficient route to skipped dienes based on the gold-catalyzed reaction of vinyldiazo compounds and alkenylsilanes. In most cases this transformation proceeds with complete regio-and stereoselectivity with the silyl group serving as a regio-and stereocontrolling group. Alkynylsilanes are also well suited for the current transformation providing differently substituted skipped enynes in moderate yields.  Organic Letters pubs.acs.org/OrgLett Letter Desarrollo Regional (FEDER) (Grants PID2019-107469RB-I00, PID2019-106184GB-I00, and RED2018-102387-T) is gratefully acknowledged. K.Y. was supported by a Japan Public-Private Partnership Student Study Abroad Program TOBI-TATE Young Ambassador Program. We also acknowledge the technical support provided by Servicios Científico-Técnicos de la Universidad de Oviedo. We also thank Prof. J. M. González (Universidad de Oviedo) for helpful discussions.